Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status
Claim 1-5,7-8,10-11 and 13-20 are pending and examined.
Allowable Subject Matter
Claims 7 and 13 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Priority
This application is a continuation application of U.S. Application Serial No. 19/176,900, filed April 11, 2025, which is a divisional application of U.S. Application Serial No. 17/696,267, filed March 16, 2022, which is a continuation application of U.S. Application Serial No. 16/163,055, filed October 17, 2018.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
A. Claims 1-5, 8, 10-11, 14-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Horowitz et al. (US 2004/0157802 A1) in view of Kuramata et al. (Environ. Chem. 2016, 13, 723–731 – cited in 9/22/2025 IDS), De Block et al. (The EMBO Journal 6(9):2513-2518. (1987) – cited in 9/22/2025 IDS), and Christ et al. (Nat Plants. 2017 December ; 3(12): 937–945. doi:10.1038/s41477-017-0061-1).
Claimed invention
Claim 1 is drawn to a method of killing or inhibiting the growth of an infectious agent other than Escherichia coli, comprising contacting the infectious agent with an effective amount of arsinothricin or a salt thereof, and an inhibitor of arsinothricin N-acetyltransferase, wherein the infectious agent expresses arsinothricin N-acetyltransferase.
Claim 11 is drawn to a method of treating an infection in a subject caused by an infectious agent other than Escherichia coli, comprising administering to the subject arsinothricin or a salt thereof at an effective dose in the range of from about 0.001 to about 100 mg/kg of body weight per day in combination with an inhibitor of arsinothricin N-acetyltransferase, wherein the infectious agent expresses arsinothricin N-acetyltransferase.
Prior art
Horowitz teaches novel antimicrobial compositions containing analogues of L-methionine-SR-sulfoximine (MSO) having general formula 1
PNG
media_image1.png
124
82
media_image1.png
Greyscale
. See Fig. 6. The analogues are effective for treating intracellular pathogen infections, specifically Mycobacterium infections (e.g., M. bovis, M. tuberculosis, etc.). See abstract; see also 0022. The structurally related analogues work by inhibiting the mycobacterium glutamine synthetase (MbGS). One specific effective analogue is phosphinothricin (PPT) having the structure
PNG
media_image2.png
162
84
media_image2.png
Greyscale
. See 0037, last sentence; see also 0039.
While Horowitz teaches that phosphinothricin as an MSO analogue is effective for treating Mycobacterium infection including M. tuberculosis and M. bovis, Horowitz does not expressly teach 1) arsinothricin or 2) an inhibitor of arsinothricin N-acetyltransferase, wherein the infectious agent expresses arsinothricin N-acetyltransferase.
Regarding 1) arsinothricin:
Kuramata found 2 novel compounds produced by bacteria in the rhizospheres of rice plants. One of them, arsinothricin (AST), is an arsenic mimetic of phosphinothricin (PPT). See abstract. It was named arsinothricin due to its similar structure to phosphinothricin. See p. 2nd col. 1st full paragraph.
PNG
media_image3.png
182
90
media_image3.png
Greyscale
vs.
PNG
media_image4.png
162
84
media_image4.png
Greyscale
. AST was shown to be absorbed by E. coli and possess toxic antibacterial efficacy against it. See abstract. Results suggest that this is because of AST's structural similarity to PPT. See p. 729, 1st paragraph, last sentence.
One of ordinary skill in the art (POSA) would have found it obvious to inhibit the growth of or treat infections caused by M. tuberculosis or M. bovis because Horowitz teaches that MSO analogues such as phosphinothricin (PPT) are effective agents for treating mycobacterium infections such as infections caused by M. tuberculosis or M. bovis while Kuramata teaches that arsinothricin (AST) is an antibacterial analogue and mimetic of PPT. The POSA would have had a reasonable expectation of success in for inhibiting M. tuberculosis or M. bovis because AST is an antibacterial agent that is structurally very close to PPT (
PNG
media_image3.png
182
90
media_image3.png
Greyscale
vs.
PNG
media_image5.png
162
84
media_image5.png
Greyscale
) and is described as having PPT mimetic activity. Thus, one of ordinary skill in the art would have reasonably believed that AST would, like PPT, possess antibacterial efficacy against infections cause by Mycobacterium.
Regarding 2) an inhibitor of arsinothricin N-acetyltransferase, wherein the infectious agent expresses arsinothricin N-acetyltransferase (AAT):
As outlined above, arsinothricin (AST) is a close structural mimetic of phosphinothricin (PPT). It was known that resistance against PPT develops via expression of phosphinothricin acetyltransferase (PAT), an enzyme with promiscuous/cross-substrate action upon structurally related substrates through N-acetylation of the free -NH2 group of the substrate.
De Block teaches the cloning and characterization of a bialaphos resistance gene (bar) from Streptomyces hygroscopicus that encodes phosphinothricin acetyltransferase (PAT), an enzyme involved in the bialaphos biosynthetic pathway. De Block further discloses that PAT acetylates the free -NH2 group of phosphinothricin (PPT), thereby detoxifying the compound and preventing autotoxicity in the producing organism. (See De Block, p. 2513, second column, second paragraph.) Additionally, Christ teaches BAR/PAT acetyltransferases exhibit promiscuous N-acetyltransferase activity toward multiple substrates beyond PPT, including structurally different amino acid compounds, thereby demonstrating that such enzymes are not substrate-exclusive. (See Christ: abstract, pp. 1-2.) Given that AST is a close structural analog and mimetic of PPT, the POSA would recognize that PAT expression or expression of other known enzymes that acetylate the free -NH2 group of AST would be a concern for developing resistance to structural analogs of PPT such as AST. In view of these teachings, the POSA would have reasonably expected the bacteria expressing PAT would be capable of acetylating other compounds with a free -NH2 group and structural similarity to PPT such as arsinothricin. Accordingly, it would have been obvious to treat bacterial infection by isolating and testing the bacterium to identify whether the infecting bacterium expresses phosphinothricin N-acetyltransferase (PAT) or other enzymes that acetylate the free -NH2 group of AST, with a reasonable expectation that such expression could impart resistance by acetylation of arsinothricin. The POSA would reasonably seek to inhibit PAT/AAT in the expressing bacteria with an inhibitor thereof by combining the inhibitor with AST treatment as protection against AST acetylation.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claims 8, 14-16, and 20 each require the infectious agent to express phosphinothricin N-acetyltransferase (PAT) or arsinothricin N-acetyltransferase (AAT). These are met by the rejection as described above.
Regarding Claims 2-4, 10, 18 and 19, Horowitz teaches antimicrobial treatment of M. bovis and M. tuberculosis as outlined above.
Regarding Claim 5, wherein the infections agent does not express phosphinothricin N-acetyltransferase. Horowitz does not mention that these transferase is present. Additionally, there is no evidence that each of these transferases are necessarily expressed by M. tuberculosis and M. bovis of Horowitz. Lastly, one of ordinary skill in the art would have reasonably expect that arsinothricin would be effective in Mycobacterium that lacks expression of the claimed transferases because the combination of Horowitz and Kuramata suggests the use of AST for treating Mycobacterium.
Regarding Claim 11, comprising administering to the subject arsinothricin or a salt thereof at an effective dose in the range of from about 0.001 to about 100 mg/kg of body weight per day. Horwitz teaches MSO antimicrobial administration to animals at dose amounts of 1.56, 3.13, 6.25, 12.5, 24, 50, 100 mg/kg/day. See Table 2 at p. 5.
Regarding Claim 14, comprising administering to the subject arsinothricin or a salt thereof in combination with an inhibitor of arsinothricin N-acetyltransferase in unit dosage form containing about 0.05 to about 10000 mg of each of arsinothricin or a salt thereof or the inhibitor of arsinothricin N-acetyltransferase per unit dosage form. Given that treatment of a human is disclosed (see Horwitz, Claim 12), and disclosed dose amounts of 1.56, 3.13, 6.25, 12.5, 24, 50, 100 mg/kg/day (see Table 2 at p. 5), the POSA would have reasonably considered treatment of an average sized human man at ~90 kg with who has an infection. Thus, the POSA would easily calculate the amount based on his weight and arrive at the claimed amount, e.g., 6.25 mg times 90 is 563 mg. The POSA would reasonably understand that the acetyltransferase inhibitor amount may be adjusted to optimize protection of AST.
Regarding Claim 15, comprising administering to the subject arsinothricin or a salt thereof in combination with an inhibitor of arsinothricin N-acetyltransferase to achieve a peak plasma concentration of from about 0.25 to about 200 μM of each of arsinothricin or a salt thereof or the inhibitor of arsinothricin N-acetyltransferase per unit dosage form. Horwitz teaches antimicrobial activity of MSO analogues at concentrations of 10, 20, 100, 200, 1000, 2000 μM. See 0028. The POSA would have reasonably sought to administer AST at amounts to obtain plasma concentrations of the MSO analogue disclosed as providing antimicrobial effect. The POSA would reasonably understand that the acetyltransferase inhibitor amount may be adjusted to optimize protection of PPT. This meets the limitation of Claim 16 wherein the therapeutically useful and effective concentration range of at least about 1 mg/ml of arsinothricin. For example, 10μM of arsinothricin corresponds to 2.2507 mg/ml.
Regarding Claim 20, further comprising isolating the infectious agent, testing the infectious agent for the expression of phosphinothricin N-acetyltransferase and/or arsinothricin N-acetyltransferase, and administering to the subject an inhibitor of phosphinothricin N- acetyltransferase or arsinothricin N-acetyltransferase. As outlined above, it would have been obvious to treat bacterial infection by isolating and testing the bacterium to identify whether the infecting bacterium expresses phosphinothricin N-acetyltransferase (PAT), with a reasonable expectation that such expression could impart resistance by acetylation of arsinothricin. This also meets the limitation of Claim 8.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant’s arguments that the references fail to teach AAT are not persuasive because the prior art suggests AST is close structural to PPT and PAT acetylates free NH2 groups on such compounds. The specification does not limit the AAT to any structure but refers to it functionally. Thus, because it was known that PAT is promiscuous and acts on many different substrates, it may meet the AAT limitation as claimed.
C. Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Horowitz et al. (US 2004/0157802 A1) in view of Kuramata et al. (Environ. Chem. 2016, 13, 723–731 – cited in 9/22/2025 IDS) and Christ et al. (Nat Plants. 2017 December ; 3(12): 937–945. doi:10.1038/s41477-017-0061-1) as applied above, taken further in view of Pohl et al. (US PG-PUB 2005/0214251).
Claimed invention
Claim 17 limits claim 11, further comprising administering arsinothricin via sublingual, vaginal or spinal route.
Prior art
The disclosures for Horwitz and Kuramata are described above. Their combination suggests treatment of infection by using of AST for inhibiting M. tuberculosis or M. bovis. However, their combination does not expressly teach administration sublingually.
However, sublingual administration of drugs was already known for providing therapeutic agents with rapid onset. See Pohl, abstract, 0010. A POSA would have sought to administer AST sublingually in order to achieve faster systemic absorption and therapeutic effect, with a reasonable expectation of success, since sublingual delivery was a predictable and established route for administering drugs.
Terminal Disclaimer
The terminal disclaimer filed on 4/10/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,298,335 B2 and U.S. Patent No. 12,303,485 B2 have been reviewed and is accepted. The terminal disclaimer has been recorded.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
Prosecution Insights